This project examines the physiological effects and the underlying biochemical mechanisms of the action of delta opioid peptide DADLE in cellular survival. In this fiscal year, we found that DADLE completely blocks the dopamine and tyrosine hydroxylase loss induced by a high dose of methamphetamine. The involvement of p53 in this action of DADLE is, however, uncertain. In PC12 cells, DADLE is anti-apoptotic in pM to nM concentrations whereas is cytotoxic in the micromolar range. The anti-apoptotic action of DADLE is related to an increase in the ERK phosphorylation and the cytotoxic action of DADLE is related to the activation of Fas ligand. In CD-1 mice, methamphetamine causes an increase of Bax translocation from cytosol into mitochondria and an increase of mitochondrial cytochrome c release into the cytosol. DADLE blocks the Bax translocation and cytochrome c release caused by methamphetamine. In working isolated rabbit hearts as well as the rat hearts, preconditioning of the isolated preparation with DADLE confers myocardial tolerance to ischemia. This action of DADLE was blocked by a delta-2 opioid receptor antagonist. These results suggest that the underlying protective action of DADLE may involve the alteration of the dynamics of Bax and that DADLE may have important clinical implications against degenerative diseases in the central nervous sytem as well as in the periphery.